17alpha-oxygenated-b-norpregn-4-ene-3, 20-diones



Patented May 7, 1968 1 cu 3,382,253 3 17Ot-0XYGENATED'B'NORPREGN c=o I 0 CH 4-ENE-3,20-DIONES c 1 2k Kenneth G. Holden, Stratford, N.J., and James F. 3 3

Kerwin, Broomall, Pa., assignors to Smith Kline & 5 French Laboratories, Philadelphia, Pa., a corporation r of Pennsylvania cu can No Drawing. Filed Oct. 19, 1964, Ser. No. 404,937 3 6 Claims. (Cl. 260-3405) 7 VIII v A solution of l6a,l7a-isopropylidenediox regnenolone ABSTRACT OF THE DISCLOSURE acetate (IV) in acetic acid is oxidized with c liromium tri- Cyclic k t l f 16 ,17 -dih d -B- -4- oxide. The resulting products are the 5-oxo-5,6-seco-6- 3,20-diones and l7a-acetoxy-B-norpregn-4-ene-3,ZO-dione carboxylic acid (V) and 7-oxo-l6u,l7m-isopropylidenediare prepared by ring-contraction of the corresponding 3- oxypfegnenolofle acetate- The $600 compound is treated acetoxypregn-5-ene-3,20-diones. The products are hydrowith benzoyl chloride and pyrindine to simultaneously lyzed -to the alcohols and possess progestational activity. enolize, ring-close, and lactonize to give 3fi-acetoxy-5B- hydroxy 1604,1701 isopropylidenedioxy oxo-B-norpregnane-6/3-carboxylic acid ,8-lactone (VI). Fusion of this The present invention relates to new 17a-oxygenated- 20 compound results in elimination of carbon dioxide. The

B-norpregn-4-ene-3,20-diones having progestational activacetate group of the resulting B-norpregnenolone acetate ity. In particular, the invention relates to 17a-hydroxy and (VII) is then selectively hydrolyzed with, for example, 17oc-lOWe1 acyloxy-B-norpregn-4-ene-3,20-diones, 160L,170tpotassium hydroxide, and the resulting 3-alcohol is subdihydroxy-B-norpregn-4-ene-3,ZO-dione, and to cyclic jected to Oppenauer oxidation conditions, e.g., aluminum ke tals of 16a,17a-dihydroxy-B-norpregn-4-ene-3,20-dione. isopropoxide and a ketone such as cyclohexanone, for The compounds of the invention thus may be repreoxidation to the product VIII. This compound has been sented by the following structural formulas: found to possess progestational activity when evaluated r r C=O C= C=O 1 lj- .-cu on ,on

:3 a c 3 OH I II III wherein: in animals according to standard evaluation procedures. R is methyl or phenyl; and Heating 16e,l7a-isopropylidenedioxy B norpregn-4- R is hydrogen or acetyl. ene-3-20-dione in 90% formic acid at 40 C. for about The compounds of the invention are prepared from twenty hours cleaves the ketal group and results in the compounds having a 6-membered B-ring, by means of a formation of a l6-formate, which is then hydrolyzed to ring-opening and ring-closure sequence that results in the the 160:,17oc-di0ll1 by basic hydrolysis. loss of a carbon atom as carbon dioxide. This sequence of A B-norpregn-4-ene-3,20-dione of Formula I in which reactions is illustrated below for the preparation of 16a, R is phenyl is prepared by starting with a ketal formed 17a-isopropylidenedioxy B n0rpregn-4-ene-3,20-dione from acetophenone and 16oz,l7a-dihydroxypregnenolone (VIII). acetate and carrying out the same reaction sequence as CH CH described above. I 3 l 3 When l7a-acetoxypregnenolone acetate is used as the 6:0 starting material, 17 ot-acetoxy B norpregn-4-ene-3,20-

C ,cu dione(Formula III, in which R is acetyl) is produced. 3 -o cl-i Hydrolysis of the acetate function by refluxing in a base such as methanolic potassium hydroxide results in the 06H COCL formation of 17a-hydroxy 'B norpregn-4-ene-3,ZO-dione 353C300 i 0 ETZW (Formula III, in which R is hydrogen).

3 It will be apparent to one skilled in the art of chemistry Iv v that the starting materials for the preparation of the compounds of the invention may have certain variants thereof, l and that products resulting therefrom may also have such CH variants. For example, if, instead of utilizing the acetone --o ketal of 16:1,17u-dihydroxypregnenolone acetate (IV), one uses the homologous 2-butanone or 3-pentanone ketal as starting materials, the correspondingly homologous 1- methylpropylidenedioxy and 1 ethylpropylidenedioxy 3 0 products, respectively, are produced.

-In addition it will be obvious that instead of utilizing VI 17a-acetoxy-B-norpregn-4-ene-3,20-dione as starting material, the 17a-propionate, butyrate, or isobutyrate can be 3 employed. The products will thus be the l7apropionate, butyrate, and isobutyrate, respectively, of 17a-hydroxy-B- norpregn-4-ene-3,20-dione.

These above-mentioned variations are obvious to one skilled in the art of organic chemistry and are thus considered to be the full equivalents of the compounds specifically claimed.

The following experimental procedures illustrate the best mode of preparing the compounds of the invention, but are to be considered as merely illustrative thereof, and not limiting of the scope of the invention.

Example 1.16 x, 17 isopropylidenedioxy-B-norpregn- 4-ene-3,20-dione To a solution of 6 g. of 16a,Hut-isopropylidenedioxypregnennolone acetate [G. Cooley, B. Ellis, F. Hartley and V. Pe-trow, J. Chem. Soc., 4373 (1955)] in 60 ml. of glacial acetic acid is added 3.77 g. of chromium trioxide in ml. of 50% aqueous acetic acid. The addition is carried out during 1 hour with stirring at 55 C. After an additional 2 hours at 55, the reaction mixture is cooled, treated with 3.7 ml. of methanol to destroy excess oxidant, and concentrated at reduced pressure. The concentrate is diluted with 10 volumes of water and extracted with ether. After washing the organic extracts with aqueous sodium carbonate solution, they are combined, dried and evaporated to a residue of 7-oxo-16a,Not-isopropylidenedioxypregnenolone acetate, M.P. 173-175 .5 after recrystallization from acetone-hexane. The aqueous sodium carbonate phases are combined, acidified with hydrochloric acid and extracted with ether. Combination, drying and evaporation of the ether extracts gives crude 3,8- acetoxy 160:,17a isopropylidenedioxy 5,20 dioxo 5, 6-secopregnan-6-oic acid, which is used directly in the next step without further purification.

A solution of 4.0 g. of crude 3,6-acetoxy-16a,17u-isopropylidenedioxy-S,20-dioxo-5,6-secopregnan-6-oic acid in 25 ml. of pyridine is treated with 2.6 ml. of benzoyl chloride. After 48 hours at room temperature the reaction mixture is poured into 250 ml. of water and extracted with ether. The ether extracts are washed with 4% sodium hydroxide and 5% sodium bicarbonate solutions, combined, dried and evaporated to give 3,8-acetoxy- 5 8 hydroxy 160:,17ot isopropylidenedioxy 20 oxo- B-norpregnane-6fl-carboxylic acid }8-lactone, M.P. 153- 155 (dec.) after recrystallization from acetone-hexane. 3B acetoxy 5B hydroxy 16a,17a isopropylidenedioxy-20-oxo B norpregnane-6fl-carboxylic acid p-lactone (1.1 g.) is heated above its melting point for minutes under a nitrogen atmosphere. The cooled product is crystallized from methanol and then from acetone-hexane to give 16a,17u-isopropylidenedioxy-B-norpregnenolone acetate, M.P. 169-171".

A solution of 2.0 g. of 16a,17a-isopropylidenedioxy-B- norpregnenolone acetate in 60 ml. of 95% ethanol containing 6 g. of potassium hydroxide is refluxed under a nitrogen atmosphere for 2 hours. The reaction mixture is concentrated at reduced pressure, poured into 10 volumes of water and extracted with methylene chloride. Drying and evaporation of the methylene chloride extracts gives 160:,170: isopropylidenedioxy B norpregnenolone, M.P. 184.5-l86 after recrystallization from ligroin.

A solution of 1.5 g. of 16a,17u-isopropylidenedioxy-B- norpregnenolone in 250 ml. of toluene containing 1.0 g. of aluminum isopropoxide and 20 ml. of cyclohexanone is slowly distilled under a nitrogen atmosphere during 2 hours so that the reaction mixture is reduced to a volume of about 50 ml. After cooling, the reaction mixture is poured into 150 ml. of cold 5% hydrochloric acid and extracted with ether. The ether extracts are washed with dilute sodium bicarbonate solution, combined, and steamdistilled until the distillate is clear. The nonvolatile aqueous mixture is cooled and extracted with ether-ethyl acetate. Drying and evaporation of the organic extracts yields the crude product which is purified by crystallization from acetone-hexane to give pure 16a,17a-isopropylidenedioxy-B-norpregn-4-ene-3,20 dione, M.P. 187l89.

Example 2.--16a,17tx-dihydroxy-B-norpregn-4-ene- 3,204iione A solution of 16a,17u-isopropylidenedioxy-B-norpregn- 4-ene-3,20-dione (1 g.) in 50 ml. of formic acid is heated at 40 for 20 hours. The cooled reaction mixture is diluted with 10 volumes of water and extracted with methylene chloride. Evaporation of the methylene chloride extracts gives the l6-formate of the title compound. The 16-formate is dissolved in 40 ml. of methanol and refluxed with 10 ml. of 10% aqueous sodium carbonate solution for 2 hours. The warm reaction mixture is diluted with 5 volumes of water, cooled and filtered to give the title product.

Example 3.16a,17u-(l-phenylethylidenedioxy)-B- norpregn-4-ene-3,20-dione This compound is prepared according to the procedure of Example 1. To a solution of 6.6 g. of 16l1,170L-( 1- phenylethylidenedioxy)pregnenolone acetate in 60 ml. of glacial acetic acid is added 3.77 g. of chromium trioxide in 10 ml. of 50% aqueous acetic acid. The reaction is carried out and worked up as in Example 1 to give 3,6- acetoxy :,1701. (l-phenylethylidenedioxy)5,20-dioxo- 5,6-secopregnan-6-oic acid. This seco compound is dissolved in 25 ml. of pyridine and 2.6 ml. of benzoyl chloride is added. After standing 48 hours at room temperature, the reaction is worked up to give 3;3-acetoxy-5 3- hydroxy l6a,l7a (l phe-nylethylidenedioxy) 20-oxo- B-norpregnane-6p-carboxylic acid fi-lactone.

The lactone is heated above its melting point for 15 minutes in a nitrogen atmosphere and then crystallized to give l6a,17a (l-phenylethylizlenedioxy)-B-norpregnenolone acetate, which is refluxed in 60 ml. of 95 ethanol containing 6 g. of potassium hydroxide for 2 hours. The work-up gives 16a,17u-(l-phenylethylidenedioxy)-l3-norpregnenolone.

A solution of this compound is 250 ml. of toluene containing 1.0 g. of aluminum isopropoxide and 20 ml. of cyclohexanone is slowly distilled under nitrogen during 2 hours until one-half the original volume remains. The reaction mixture is then worked up as in Example 1 to give the title product, 16a,17a-(l-phenylethylidenedioxy)-B-norpregn-4-ene-3,20-dione.

Example 4.17a-acetoxy-B-norpregn-4-ene-3,20-dione Starting with 30 g. of 17a-acetoxypregnenolone acetate there is obtained 7-oxo-17ot-acetoxypregnenolone acetate, M.P. 235236.5 from acetone-hexane, and crude 36,17- diacet0xy-5,20 dioxo-S,6-secopregnan-6-oic by oxidation as described in Example 1.

The crude seco acid (18.3 g.) is lactonized with benzoyl chloride in pyridine, as described in Example 1, to give crude 33,170: diacetoxy 5 ti hydroxy 20 0x0 B-norpregnane-6fl-carboxylic acid fi-lactone. By heating this material (21 g.) at 190 under nitrogen for 15 minutes there is obtained 17a-acetoxy-B-norpregnenolone acetate, M.P. 212.5-214 from acetone.

Selective saponification of the 3 8-acetoxy group is carried out as follows. A solution of 11 g. of 17u-acetoxy- B-norpregnenolone acetate in 800 ml. of methanol is treated dropwise with 1.54 g. of potassium hydroxide in 10 ml. of water. After stirring for 2 hours at room temperature the reaction mixture is concentrated under reduced pressure and cooled. The product is collected by filtration and recrystallized from methanol to give acetoxy-B-norpregnenolone, M.P. 241-2435. Oppenauer oxidation of 5.2 g. of 17a-acetoxy-B-norpregnenolone, as described in Example 1, gives l7a-acetoxy-B-norpregn-4- ene-3,20-dione, M.P. 2082l0, from acetonehcxane.

Example 5.17a-hydroxy-B-norpregn-4-ene,3,20-dione A solution of 1 g. of 17a-aeetoxy-B-norpregn-4-ene-3, ZO-dione in 30 ml. of methanol is heated to reflux and a solution of 0.175 g. of potassium hydroxide in 5 m1. of

Water is slowly added over a 30 minute period. After re- 5 fiuxing for 2 hours the solution is cooled, poured into 10 volumes of Water and extracted with methylene chloride. Drying and evaporation of the methylene chloride extracts gives the title product, which is purified by recrystallization from acetone-hexane.

We claim:

1. A chemical compound selected from the group consisting of steroids of the formula:

CH CH wherein:

References Cited UNITED STATES PATENTS 3,072,681 1/1963 Kerwin 260-343.2 3,284,505 11/1966 Holden et a1. 260-586 3,287,412 11/1966 Fare et a1. 260-586 3,293,300 12/1966 Fare et a1 260-586 NICHOLAS S. RIZZO, Primary Examiner. J. H. TURNIPSEED, Assistant Examiner. 

